Association of interleukin 1 beta polymorphisms and haplotypes with Alzheimer's disease

(1)

Association of interleukin 1

β

polymorphisms and haplotypes with

Alzheimer's disease

Spencer Luiz Marques Payão

a,d,

⁎

, Gisela Moraes Gonçalves

a

, Roger William de Labio

d

, Lie Horiguchi

d

,

Igor Mizumoto

d

_{, Lucas Trevizani Rasmussen}

d

_{, Marcela Augusta de Souza Pinhel}

e

_,

Dorotéia Rossi Silva Souza

e

, Marcelo Dib Bechara

f

, Elizabeth Chen

b

, Diego Robles Mazzotti

b

,

Paulo Henrique Ferreira Bertolucci

c

, Marília de Arruda Cardoso Smith

b

a_{Universidade do Sagrado Coração, USC, Bauru, São Paulo, Brazil}

b_{Disciplina de Genética, Departamento de Morfologia, Universidade Federal de São Paulo, Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, Brazil}

c_{Disciplina de Neurologia, Ambulatório de Neurologia do Comportamento, Universidade Federal de São Paulo, Escola Paulista de Medicina (UNIFESP/EPM), São Paulo, Brazil} d_{Disciplina de Genética, Hemocentro, Faculdade de Medicina de Marilia (FAMEMA), São Paulo, Brazil}

e_{Núcleo de Pesquisa em Bioquímica e Biologia Molecular da Faculdade de Medicina de São José do Rio Preto, Brazil} f_{Faculdade de Medicina da Universidade de Marília (UNIMAR), São Paulo, Brazil}

a b s t r a c t

a r t i c l e

i n f o

Article history:

Received 22 September 2011

Received in revised form 7 February 2012 Accepted 16 March 2012

Keywords:

Alzheimer's disease Interleukin-1β

Polymorphisms Haplotypes Receptor antagonist

Our study aimed to associateIL-1βandIL-1RNpolymorphisms with AD disease in comparison with elderly control group from São Paulo—Brazil. We genotyped 199 Alzheimer's disease (AD) patients, 165 elderly control and 122 young control samples, concerning VNTR (IL-1RN) and−511C > T and−31T > C (IL-1β) polymorphisms. Ourﬁndings revealed that−511C/−31T/2-repetitions VNTR haplotype had a protective effect for AD when compared to EC (p = 0.005), whereas−511C/−31C/1-repetition VNTR haplotype was associated as a risk factor for AD (p = 0.021). Taken together, we may suggest that there is a relevant role of IL-1 genes cluster in AD pathogenesis in this Brazilian population.

1. Introduction

Alzheimer's disease (AD) is a progressive and neurodegenerative

disorder that causes loss of memory, mental confusion and several

cog-nitive disturbances. Sporadic cases frequently present late-onset disease

whereas familial cases usually show early-onset disease (Khachaturian,

1985; Kay, 1986). There are evidences that at least four genes are

involved in AD etiology: mutations in

APP,

PSEN1

and

PSEN2

genes

have been well documented in the literature and

ε4 allele of

APOE

is

considered an expressive risk factor for late-onset AD (Pericak-Vance

et al., 1991; Dursun et al., 2008; Feulner et al., 2010).

The in

ﬂ

ammatory process also seems to contribute to AD. Cytokines

and other proteins associated to in

ﬂ

ammation were found in AD

patients' brains. The interleukin 1 (IL-1) is a pro-in

ﬂ

ammatory cytokine

usually produced in the brain by the microglia and seems to play an

important role in the AD pathogenesis (Kornman, 2006). In humans,

the interleukin 1 cytokine family consists of three genes located on

the long arm of chromosome 2 that encodes for IL-1α, IL-1β

and the

interleukin 1 receptor antagonist (RN) in a region of approximately

430 kb (Grif

ﬁ

n et al., 2000). Each of these genes shows single nucleotide

polymorphisms (SNPs) that affect their expression by increasing either

the rate of mRNA synthesis or stability.

Some

ﬁ

ndings have shown a reduced liberation of the three

prin-cipal pro-in

ﬂ

ammatory cytokines (IL-1, IL-6 and TNF) and a presence

of a down-regulation system of the outlying immune response in the

last phase of the disease has been proposed (Sala et al., 2003). IL1A

2,2 polymorphism has been identi

ﬁ

ed as a risk factor in

neuropathologi-cally con

ﬁ

rmed AD patients from four centers in the United Kingdom

and United States (Nicoll et al., 2000). A strong association between

IL1A T/T genotype with early-onset AD disease has been reported in

188 patients from Centers for Memory Disorders in Northern Italy

(Grimaldi et al., 2000). Moreover, the combination of IL1A

polymor-phism with IL1B polymorpolymor-phism at position +3953 (exon 5) increased

the risk factor and modulated the age-onset of AD (Sciacca et al., 2003).

In a Japanese-American cohort of 943 men from Honolulu

–

Asia

Aging Study, a signi

ﬁ

cant association between the IL1B

−

_{511C > T}

and IL1RN polymorphisms with late-onset AD has been detected,

Journal of Neuroimmunology 247 (2012) 59–62

⁎Corresponding author at: Laboratório de Genética, Hemocentro, Famema, Rua Lourival Freire, 240, Bairro Fragata, CEP 17519–050, Marília, São Paulo, Brazil. Tel.: +55 14 34021856; fax: +55 14 34330148.

doi:10.1016/j.jneuroim.2012.03.012

Contents lists available at

SciVerse ScienceDirect

Journal of Neuroimmunology

j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / j n e u r o i m

Open access under the Elsevier OA license.

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suggesting that these variants might confer an increased risk for AD

(Yucesoy et al., 2006).

Controversial

ﬁ

ndings concerning the relationship between IL1B

polymorphisms and AD have been reported. A signi

ﬁ

cant association

of

−

_{511 TT genotype with late-onset AD has been reported in Taiwan}

Chineses and in Italians (Grimaldi et al., 2000; Licastro et al., 2000;

Wang et al., 2005) while other studies did not reply these association

ﬁ

ndings (Ehl et al., 2003; Ma et al., 2003; Ravaglia et al., 2006; Wang

et al., 2007). An association study of AD with IL-1β

(

−

_{31T > C) in a}

Chinese population did not detect an involvement of this

polymor-phism in late-onset AD pathogenesis (Ma et al., 2003).

The substitution as position IL-1β

(

−

_{511C > T) in the promoter}

region of IL-1β

regulates the production of IL-1β

and the

in vitro

expression of C/C genotype carriers was lower than that of C/T or T/T

carriers (Santtila et al., 1998). This is consistent with the hypothesis

that an increase in IL-1β

expression increases the rate of Aβ

deposition

and cytokine-mediated in

ﬂ

ammation in predisposed individuals.

In the present study, we investigated a possible association among

the interleukin 1

β

(

−

_{511C > T and}

−

_{31T > C) and the interleukin 1}

receptor antagonist with late-onset AD and controls.

2. Materials and methods

2.1. Subjects

Peripheral blood samples were obtained from 199 AD patients,

165 elderly control (EC) and 122 young control (YC) individuals.

The three subject groups had similar ethnic origins, being 95% with

major European origin, 2.5%, with Japanese origin and 2.5% with

mixture origin. The mean age and standard deviation of the samples

were 75.31 ± 7.92 years for AD group composed by 69 men and 130

women; 71.67 ± 8.13 years for EC group composed by 55 men and

110 women and 20.76 ± 1.63 for YC group composed by 42 men

and 80 women. AD patients were selected according to

NINCDS-ADRDA criteria for probable AD (Morris, 1993). Vascular dementia

was excluded by a Hachinski score of 5 or higher and by

neuro-imaging (Hachinski et al., 1975). Patients and controls were from

São Paulo City and all subjects gave informed consent to participate

in this study that was approved by the local ethics committee.

2.2. Genotyping

Genomic DNA was extracted from blood samples using QIAamp

DNA Blood Midi Kit QIAGEN

™

(Qiagen, Germany), following

manu-facturer's instructions. Genotypes were determined by a polymerase

chain reaction (PCR) and restriction fragment length polymorphism

(RFLP).

2.2.1. IL1β

−

31T > C

The 240 base pairs (bp) fragment was ampli

ﬁ

ed from genomic

DNA using the oligonucleotides ST 5

′

-AGAAGCTTCCACCAATACT -3

′

and AC 5

′

-TAGCACCTAGTTGTAAGGA-3

′

(22). PCR conditions involved

an initial denaturation of 94 °C/5 min followed by 27 cycles of 94 °C/

45 s, 53 °C/45 s, 72 °C/1 min and a

ﬁ

nal extension period at 72 °C/

7 min. The ampli

ﬁ

cation products (240 bp) were digested with

Alu1

(Fermentas, USA) and visualized in 3% agarose gel, stained with

ethi-dium bromide and analyzed on Alpha Imager 2200 (Alpha Innotech

Corporation

™

).

2.2.2. IL1β

−

511C > T

IL-1β

(

−

_{511C > T) genotypes were determined with a PCR and}

RFLP. The 189 bp fragment was ampli

ﬁ

ed from genomic DNA using

the oligonucleotides F 5

′

-CTGCATACCGTATGTTCTCTGCC-3

′

and R 5

′

-GGAATCTTCCCACTTACAGATGG-3

′

(23). PCR conditions involved an

initial denaturation of 94 °C/5 min followed by 30 cycles of 94 °C/

30 s, 60 °C/30 s, 72 °C/30 s and a

ﬁ

nal extension period at 72 °C/

5 min. The ampli

ﬁ

cation products (189 bp) were digested with

AvaI

(Fermentas, USA) and visualized in 2% agarose gel, stained with

ethi-dium bromide and analyzed on Alpha Imager 2200 (Alpha Innotech

Corporation

™

).

2.2.3. IL1RN/VNTR

Fragments containing variable number of identical tandem repeat

of 87 bp were ampli

ﬁ

ed using the primers

ﬂ

anking the region: RNa 5

′

TCCTGGTCTGCAGGTAA 3

′

and RNb 5

′

CTCAGCAACACTCCTAT 3

′

(24).

Ampli

ﬁ

cation was performed under the following conditions: at

94 °C for 5 min; 40 cycles at 94 °C for 30 s, 60 °C for 30 s, 72 °C for

30 s, followed by one cycle at 72 °C for 5 min and cooling at 4 °C.

PCR products of 410 bp (allele 1, four repeats of the 86 bp region),

240 bp (allele 2, two repeats), 500 bp (allele 3,

ﬁ

ve repeats), 325 bp

(allele 4, three repeats) and 595 bp (allele 5, six repeats).

2.3. Statistical analysis

Allele frequencies were calculated by allele counting as described

by Emery (Emery, 1986). Hardy

–

Weinberg equilibrium was evaluated

using

χ

2

test. To assess the association between allele and morbidity,

logistic regression analysis was performed, which considered

morbid-ity as a dependent variable and allele, age and sex as covariates in the

model. Odds ratios (OR) with 95% con

ﬁ

dence intervals (CI) were also

calculated using SPSS® 18.0. For VNTR polymorphism, only subjects

with genotypes 1/1, 1/2 and 2/2 were included in the analysis. For

genotype distributions only two groups: I/I and non-I/I (I/II + II/II)

genotypes were analyzed, due to the expected small number of

sub-jects. Linkage disequilibrium (LD) and haplotype association analysis

with morbidities were performed by Haploview software (Barrett

et al., 2005). Expectation

–

Maximization algorithm was used to

esti-mate haplotype frequencies and to verify the association between

haplotypes and morbidities.

χ

2

test was used to compare haplotypes

frequencies of cases and controls concerning the morbidities studied.

Statistical signi

ﬁ

cance was accepted at p

b

0.05. 3. Results

Genotype frequencies are presented in

Table 1. Minor allele

frequencies of

−

_{511C > T,}

−

_{31T > C and VNTR polymorphisms were}

0.441, 0.455 and 0.257, respectively. All polymorphisms were within

the Hardy

–

Weinberg equilibrium in the whole population (df = 1)

(Table 1).

Using haploview software, we observed that

−

_{511C>T and}

−

_31T>

C polymorphisms were in linkage disequilibrium (D

′

=0.7336) as well

Table 1

Genotype distribution of−511C > T,−31T > C and VNTR polymorphisms and Hardy–

Weinberg Equilibrium (HWE) results, in all analyzed groups. Polymorphism Genotypes Groups

N (%)

HWE

AD EC YC 2_(p)

−31T > C C/C 57 (28.9) 54 (33.2) 45 (38.1) 2.16 (p = 0.142) C/T 93 (47.2) 81 (49.6) 48 (40.7)

T/T 47 (23.9) 28 (17.2) 25 (21.2) Total 197 163 118

−511C > T C/C 38 (20.2) 24 (15.8) 24 (21.6) 1.613 (p = 0.203) C/T 107 (56.9) 84 (55.3) 48 (43.2)

T/T 43 (22.9) 44 (28.9) 39 (35.2) Total 188 152 111

VNTR 2/2 10 (5.3) 18 (11.8) 8 (7.2) 1.737 (p = 0.188) 1/2 73 (38.8) 54 (35.6) 36 (32.4)

1/1 105 (55.9) 80 (52.6) 67 (60.4) Total 188 152 111

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as

−

_{31T>C with VNTR (D}

_′

_{=0.37) and}

−

_{511C>T with VNTR (D}

_′

₌

0.336).

Tables 2 and 3

shows the haplotype composed by IL1 beta

−

_{511C > T,}

−

_{31T > C and VNTR polymorphisms frequencies, the}

calculated Odds Ratio, the 95% Con

ﬁ

dence Interval and p value related

to comparison between AD patients and Controls . Thus, haplotype

−

_511C,

−

_{31T and VNTR2 showed a protective effect to AD in}

rela-tion to Elderly Group. On the other hand, haplotype

−

_{511 C,}

−

_{31 C,}

VNTR1 has been considered a risk factor associated to AD in relation

do Elderly Group (p

—

0.021, OR = 2.41, 95% CI: 1.15

–

5.09) as well

as and in relation to Young controls (p

—

0.028, OR = 2.81, 95% CI:

1.13 –

7.02).

Table 4

indicates studies of the IL-1β

−

_{511C > T,}

−

_{31C > T and}

IL1RN polymorphisms/haplotypes and yours effects in AD.

4. Discussion

To our knowledge, there are no reports concerning association study

of

IL1beta

polymorphisms and haplotypes with AD in the Brazilian

population.

IL1 have been found to be related to susceptibility and to

patho-genic activities in the central nervous system and in many other

immune-mediated disorders, such as AD, Parkinson's, temporal lobe

epilepsy, schizophrenia, febrile convulsions and others (Mrak and

Grif

ﬁ

nbc, 2001). Each one of our studied polymorphisms of IL 1beta

did not show association with AD in relation to Elderly and Young

Controls, but our

ﬁ

ndings agreed partially with results from Polish

(Klimkowicz-Mrowiec et al., 2009) and Chinese populations where

IL1 beta (

−

_{511C > T) and (}

−

_{31T > C) were not respectively}

associ-ated with AD late-onset (Ma et al., 2003). Furthermore our

ﬁ

ndings

also partially agreed with those from Bosco et al. from an Italian

population (Bosco et al., 2004) who reported a protective effect of

allele 2 of IL1RN in 152 sporadic AD with dementia grade

≥

₆

accord-ing to Reisberg score in relation to 136 age-matched controls.

Therefore we may suggest that this cluster is effectively involved

in AD late-onset pathogenesis in Brazilian population.

Probably IL1 up regulates expression and processing of APP, which

may in

ﬂ

uence A-beta load (beta-amyloid immunoreactivity) in the

brain of AD patients. It is also possible that the increased risk found

in previous studies could be caused by linkage disequilibrium with

other yet to be identi

ﬁ

ed polymorphism in the IL-1

α

and

β

cluster

in chromosome 2q14, present in some populations.

Likewise, IL-1β

elevated the levels of sAPP in the culture medium

of primary neurons in a dose-dependent fashion (Liu et al., 2011). In

addition to inducing IL-1β

expression and release, sAPP and Aβ

also

stimulate microglia to release biologically relevant levels of glutamate

and its cooperative excitatory amino acid

D

-serine (Wu et al., 2004,

2007).

The imbalance in the 1β/1RN ratio may result in elevated

IL-1 responses and a more severe in

ﬂ

ammation. An increased serum

level of IL1 beta has been proposed as a stage marker of the ongoing

brain neurodegeneration since aging, mild cognitive impairment

and AD (Forlenza et al., 2009).

Excess production and secretion of IL-1β

elevates neuronal

ex-pression of the precursors of each of the changes characteristic of

AD. These neurodegeneration-related precursors include

β-amyloid

precursor protein (βAPP), which may lead in vivo to deposition of

Aβ

(Sheng et al., 1996a, 1996b) and further induction of IL-1β

(Barger and Harmon, 1997); ApoE, which is present in plaques

(Sheng et al., 1996a, 1996b) and necessary for the accumulation of

Aβ

deposits (Bales et al., 1999); and hyperphosphorylated tau

(Strittmatter et al., 1994), the principal component of neuro

ﬁ

brillary

tangles. IL-1 also induces

α-synuclein (Grif

ﬁ

n et al., 2006), the Lewy

body precursor.

Therefore, taking together our

ﬁ

ndings with those from literature

we can suggest that IL-1 gene cluster polymorphisms may play a

rel-evant role in the susceptibility to Alzheimer´s disease in Brazilians.

Acknowledgements

This research was supported by Fundação de Amparo à Pesquisa de

São Paulo (FAPESP, BRAZIL) Grants number

—

06/07240-3,

09/15857-9 and 04/15273-3, Universidade do Sagrado Coração de Bauru,

Faculdade de Medicina de Marília (FAMEMA), CNPq, and CAPES.

Table 2

Haplotype association composed byIL1β−511C > T,−31T > C and VNTR polymor-phisms between AD patients and Elderly Controls (EC).

−511C > T −31T > C VNTR Haplotype frequency OR (95% CI) p

C T 1 0.395 1.00 –

C T 2 0.073 0.26 (0.10–0.66) 0.005* C C 1 0.072 2.42 (1.15–5.09) 0.021* OR: odds ratio; CI: conﬁdence interval.

*p statistically signiﬁcant.

Table 3

Haplotype association composed byIL1b−511C > T,−31T > C and VNTR polymor-phisms between AD patients and Young Controls (YC).

−511C > T −31T > C VNTR Haplotype frequency OR (95% CI) p

T C 1 0.402 1.00 –

T C 2 0.1507 1.80 (1.01–3.20) 0.05 C C 1 0.0777 2.81 (1.13–7.02) 0.028* OR: odds ratio; CI: conﬁdence interval.

*p statistically signiﬁcant.

Table 4

Summary of 8 case–control studies and one meta-analysis study of the IL-1β−511C > T,−31C > T and IL1RN polymorphisms/haplotypes and yours effects in AD. Authors *Polymorphism/**Haplotypes IL1β

Levels

Association with AD/effect

−511C > T −31C > T IL1RN

Present study ** C ** T ** 2 – Yes/protective effect to AD in relation to Elderly Group ** C ** C ** 1 – Yes/risk factor associated to AD in relation do Elderly Group

Klimkowicz-Mrowiec et al. (2009) * C > T – – – No

Ma et al. (2003) * C > T * C > T – – No

Bosco et al. (2004) * C > T – * 2 – Yes/protective effect of allele 2 in relation to age-matched controls

Bi et al. (2004) – – *1 > 2 – No

Forlenza et al. (2009) – – – ↑ Yes/a stage marker of the ongoing brain neurodegeneration

Déniz-Naranjo et al. (2008) * T – – – Yes/−511T polymorphism is an independent risk factor for AD

Di-Bona et al. (2008)meta-analysis with 16 case–control study

* T – – – Yes/−511 TT genotype on the risk of AD for Caucasian and non-Caucasian populations

Wang et al. (2005) * T – – – Yes/−511TT genotype is a risk factor for AD in Chinese and Taiwan patients

61

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